Process for preparing 2,5-diamino-4,6-dichloropyrimidine

ABSTRACT

A process for the preparation of 2,5-diamino-4,6-dichloropyrimidine, which process comprises the chlorination of 2,5-diamino-4,6-dihydroxypyrimidine with phosphorus oxychloride and a quaternary ammonium chloride or a weak tertiary amine base hydrochloride.

This invention relates to a process for the preparation of a compounduseful as an intermediate in the preparation of pharmaceuticalcompounds.

The compound 2,5-diamino-4,6-dichloropyrimidine of formula (I): ##STR1##is a useful intermediate in the preparation of antiviral nucleosideanalogues, such as those described in EP-A-242482 and 319228 (BeechamGroup p.l.c.), and via the process described in EP-A-313289 (BeechamGroup p.l.c.).

The literature reference for the preparation of this compound (Templeet. al., J. Org. Chem., 40 (21), 3141, 1975) involves a five stepsynthesis from 5-nitropyrimidine, giving a poor overall yield.Chlorination of 2,5-diamino-4,6-dihydroxypyrimidine of formula (II):##STR2## or depicted in the tautomeric form (IIA): ##STR3## withphosphorus oxychloride is described as unsuccessful.

The literature route gives a poor yield of product which renders routesutilizing the intermediate of formula (I) commercially unfavorable.

A high yielding process has now been discovered which uses phosphorusoxychloride in the presence of a quaternary ammonium chloride as thechlorinating agents.

Accordingly, the present invention provides a process for thepreparation of a compound of formula (I), as hereinbefore defined, whichprocess comprises chlorinating a compound of formula (II), ashereinbefore defined or an acid addition salt thereof with phosphorusoxychloride and a quaternary ammonium chloride or a weak tertiary aminebase hydrochloride.

The reaction is preferably carried out using the quaternary ammoniumchloride as solvent, by fusing the reagents at about 100° C. Thereaction may also be carried out in a polar inert organic solvent suchas acetonitrile, tetrahydrofuran, dioxan, nitromethane, diglyme ordimethoxyethane, preferably acetonitrile.

Examples of ammonium substituents in a quaternary ammonium chlorideinclude C₁₋₁₂ alkyl, usually C₁₋₄ alkyl, or phenyl or benzyl. Preferablya quaternary ammonium chloride is methyltriethylammonium ortetraethylammonium chloride.

Phosphorus oxychloride and a quaternary ammonium chloride are usuallypresent in amounts of from 2-10, preferably from 3-6 molar equivalentsof the compound of formula (II).

A tertiary amine weak base is, for example, N,N-dimethylaniline ordiethylaniline. The base hydrochloride is usually present in an amountof approximately 2-6 molar equivalents with respect to the compound offormula (II).

The reaction is preferably carried out at an elevated temperature offrom 30°-120 C., most preferably under reflux and/or withultrasonization at around 100° C.

Preferably the reaction is allowed to proceed for a period of greaterthan 12 hours, usually 24-30 hours.

The above described process has the advantage that it is suitable forlarge scale production of the compound of formula (I).

The compound of formula (II) is prepared from5-acetamido-2-amino-4,6-dihydroxypyrimidine, or from other corresponding5-acyl derivatives by the action of concentrated hydrochloric acid.5-acetamido-2-amino-4,6-dihydroxypyrimidine is prepared by condensingguanidine carbonate with diethyl 2-acetamidomalonate in ethanol orisopropanol.

The following Examples illustrate the invention. The followingDescription illustrates the preparation of the intermediate of formula(II).

DESCRIPTION 2,5-Diamino-4,6-dihydroxypyrimidine hydrochloride ##STR4##

5-Acetamido-2-amino-4,6-dihydroxypyrimidine (700 g crude) (ex.guanidinium carbonate, diethyl acetamido malonate and ethanol refluxed48 hours), concentrated hydrochloric acid (2 liters water), (200 ml),were heated to 70° and kept at 70°-75° for 1 hour, then cooled in an icebath. The product was filtered, washed with HCl (80 ml conc HCl in water170 ml), then acetone (1 liter), and air dried at 40° to give the titlecompound (344.5 g). Found: C 24.53, H 4.33, N 28.9 Cl 17.9; C₄ H₆ N₄ O₂·HCl·H₂ O requires C 24.4, H 4.6, N 28.5, Cl 18.0%. NMR C¹³ 84.59,115.24, 157.22 ppm DMSO MS/FAB M+H 143. Vacuum oven drying at 0.5 mm and85° C. with argon protection gave 320 g (46% yield).

EXAMPLE 1 2,5-Diamino-4,6-dichloropyrimidine ##STR5##

Dry Methyltriethylammonium chloride (500 g), (prepared in acetonitrile),phosphorus oxychloride (700 ml) and 2,5-diamino-4,6-dihydroxypyrimidinehydrochloride (200 g) (vacuum dried at 85° for 24 hours) were heatedwith stirring to 104° C. internal temperature. Hydrogen chloride gas wasevolved and the reagents slowly dissolved. The reaction mixture was keptat 105° for 28 hours, cooled and the excess phosphorus oxychloride (250ml) distilled off under vacuum up to 40° C.

The reaction mixture was poured into water (5 liters), adding ice tokeep the temperature at about 50°-55° C., 40% sodium hydroxide(approximately 1100 ml) was added with ice to keep the temperature at50°55° C., the pH adjusted to 4, and the mixture stirred for 1 hour at50°. The pH was adjusted to 7 (40% NaOH 300 ml), cooled to 35° C. andthe product was extracted with ethyl acetate (10 liters). The phaseswere filtered through CELITE separately to remove black solids and somephosphates. The aqueous phase was extracted with ethyl acetate (2×1liters).

The ethyl acetate phase was washed with brine, concentrated to 4.5liter, filtered warm through a dry silica plug (700 g 0.05 mm) to removeblack solid and color, then washed through with ethyl acetate (1 liter).

The ethyl acetate was concentrated under vacuum to approximately 2liters. The crystalline solid was filtered to yield the title compound(97.1 g). The filtrate was then concentrated to about 100 ml andfiltered again to yield 34.2 g. Total yield 131 g, (65%).

A sample was chromatographed on silica and crystallized from ethylacetate.

Found: C, 26.65, H, 2.4, N, 31.4, Cl 39.5; C₄ H₄ N₄ Cl₂ requires C,26.84, H, 2.25, N, 31.3, Cl, 39.6%.

NMR C¹³ 126.04, 145.52, 154.30 ppm DMSO MS/EI 178, 180, 182, M⁺ Cl₂pattern 143 M-Cl, 142, 115, 89, M/z, 53.

EXAMPLE 2

Dry 2,5-Diamino-4,6-dihydroxypyrimidine hydrochloride (1.8 g),tetraethyl ammonium chloride (9.8 g) (dry) and phosphorus oxychloride(5.5 ml) were heated at 105° for 20 hours. The reaction mixture wasprocessed as in Example 1 on a smaller scale to give 0.9 g (50% yield)2,5-diamino-4,6-dichloropyrimidine.

EXAMPLE 3

Dry 2,5-Diamino-4,6-dihydroxypyrimidine hydrochloride (3.6 g), dryN-ethyl-N-methyl piperidinium chloride (22 g) and phosphorus oxychloride(13 ml) were heated at 105° with stirring for 24 hours. The reactionmixture was processed as in Example 1 to give 2.27 g (65% yield) of2,5-diamino-4,6-dichloropyrimidine.

EXAMPLE 4

Diethylaniline (six equivalents) was substituted for the quaternarychloride in Example 2. High pressure liquid chromatography showed thepresence of 2,5-diamino-4-chloro-6-hydroxypyrimidine and2,5-diamine-4,6-dichloropyrimidine at approximate ratio 1:1 after 20hours.

I claim:
 1. A process for the preparation of a compound of formula (I):##STR6## which process comprises chlorinating a compound of formula(II): ##STR7## with phosphorus oxychloride and a quaternary ammoniumchloride or a weak tertiary amine base hydrochloride.
 2. A processaccording to claim 1 wherein the chlorination is with phosphorusoxychloride and a quaternary ammonium chloride.
 3. A process accordingto claim 2, wherein the quaternary ammonium chloride is used as thesolvent, fusing the reagents at about 100° C.
 4. A process according toclaim 1, 2 or 3 wherein the quaternary ammonium chloride ismethyltriethylammonium or tetraethylammonium chloride.
 5. A processaccording to claim 1 wherein the chlorination is with phosphorusoxychloride and a weak tertiary amine base hydrochloride.
 6. A processaccording to claim 5 wherein the weak base is N,N-dimethylaniline ordiethylaniline.